A convenient cyclopropanation process of oxindoles via bromoethylsulfonium salt

Article abstract of DOI:10.1016/j.tet.2018.09.042

A practical convenient conversion of oxindoles into the corresponding spirocyclopropyl oxindoles is achieved efficiently using bromoethylsulfonium salt, which is easily prepared on a large scale and is stable crystalline. This reaction of bromoethylsulfonium salt with different substituted unprotected oxindoles proceeded under mild condition and provided moderate yields.

Full text of DOI:10.1016/j.tet.2018.09.042

Accepted Manuscript
A convenient cyclopropanation process of oxindoles via bromoethylsulfonium salt
Hui Qin, Yuanyuan Miao, Ke Zhang, Jian Xu, Haopeng Sun, Wenyuan Liu, Feng
Feng, Wei Qu
PII:
S0040-4020(18)31121-9
10.1016/j.tet.2018.09.042
TET 29814
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 August 2018
Revised Date: 19 September 2018
Accepted Date: 20 September 2018
Please cite this article as: Qin H, Miao Y, Zhang K, Xu J, Sun H, Liu W, Feng F, Qu W, A convenient
cyclopropanation process of oxindoles via bromoethylsulfonium salt, Tetrahedron (2018), doi: https://
doi.org/10.1016/j.tet.2018.09.042.
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A convenient cyclopropanation process of
oxindoles via bromoethylsulfonium salt
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Hui Qin, Yuanyuan Miao, Ke Zhang, Jian Xu, Haopeng Sun, Wenyuan Liu, Feng Feng, Wei Qu
China Pharmaceutical University, Nanjing 211198, China

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Tetrahedron
journal homepage: www.elsevier.com
A convenient cyclopropanation process of oxindoles via bromoethylsulfonium salt
Hui Qina, Yuanyuan Miaob, Ke Zhanga, Jian Xua, Haopeng Sunc, Wenyuan Liud, Feng Fenga, e, f, , and Wei
Qua, e,
a Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China
b State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical
University, Nanjing 211198, China
c Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People’s Republic of China
d Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
e Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 211198, China
f Jiangsu Food and Pharmaceutical Science College, Huai’an 223003, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A practical convenient conversion of oxindoles into the corresponding spirocyclopropyl
oxindoles is achieved efficiently using bromoethylsulfonium salt, which is easily prepared on a
large scale and is stable crystalline. This reaction of bromoethylsulfonium salt with different
substituted unprotected oxindoles proceeded under mild condition and provided moderate yields.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
2-Oxindoles
Cyclopropanation
Methodology
Bromoethylsulfonium salt
———
Corresponding author.
Corresponding author.
E-mail: fengfeng@cpu.edu.cn (F. Feng), popoqzh@126.com (W. Qu)

2
Tetrahedron
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metal Mg (Scheme 2a);11 2) N-substituted spirocyclopropyl
1. Introduction
oxindoles could be synthesized via using vinyl selenone in
aqueous basic medium with cetyltrimethyl ammonium bromide
(CTAB);10f 3) cyclopropanation of indoles with vinyl diphenyl
sulfonium triflate catalyzed by zinc triflate in organic alkaline
solvents.10h
Oxindole scaffold is prevalent heterocyclic motif in numerous
naturally occurring products, marketed pharmaceuticals and
agrochemicals, which exhibit all kinds of biological activities,
such as anti-inflammatory activity,1 receptor agonists,2 protease
inhibitors (Scheme 1).3 Particularly, spirooxindoles are regarded
as “privileged structures” owing to their excellent binding ability
to many receptors,4 in which spirocyclopropyl oxindoles
(Scheme 1) are significant because such structures in drug
discovery and design can introduce potentially favorable
conformational rigidity with reasonable addition of molecular
weight and lipophilicity. Through the construciton of spiro-ring
system, spirocyclopropyl oxindoles integrate two important
pharmacophores, quaternary oxindoles5 and three-membered
cyclopropanes,6 both of which often exist in numerous bioactive
compounds showing a broad spectrum of pharmacological
activities. As a result, conformational restrained spirocyclopropyl
oxindole derivatives usually exhibit remarkable bioactivities.7
For instance, compound 4 showed nanomolar level biological
activity as HIV-1 nonnucleoside reverse transcriptase inhibitors;
compound 5 and compound 6 were found to be a progesterone
receptor modulator and an angiogenesis inhibitor; in addition,
compound of formula 7 displayed an extraordinary anticancer
activity in nanomolar level.
On the other hand, Vinylsulfonium salts12 are widely used as a
cyclization reagent in chemical synthesis. For instance, first
vinylsulfonium salts are reported as a cyclopropanation reagent
in 1966 from the Gosselck’s group;12a Lin’s team has reported a
general access to 1,1-cyclopropane aminoketones via the tandem
reaction of a-amino aryl ketones with vinylsulfonium salts in
2012.12b In addition, Huang’s research group has explored a new
strategy for access to hydroindol-5-ones containing a methylthio
group via [3+2] annulation of prop-2-ynylsulfonium salts.13
As noted above, methods of oxindoles cyclopropanation from
reported literatures still have many limitations. For example, the
above-mentioned first method usually requires two synthetic
steps with an overall poor yield; while application of the second
method often need to protect oxindole nitrogen as well as other
acidic functional groups, with unprotected oxindoles, over-
alkylation on the nitrogen is a common side reaction; despite the
third method above, which has been developed and reported by
Qian’s group in 2017, is highly effective for a series of different
substituted oxindoles, it suffers from the need to prepare and
isolate the sensitive, oily vinyl sulfonium salt-an especially
challenging problem on a large scale.
Scheme 2. Different strategies for cyclopropanation of indoles to acquire
spirocyclopropyl oxindoles.
Hence, in present work our research team describe that in fact
this cyclopropanation chemistry can be conducted without
Zn(OTf)2, which is expensive reagent and is easy to pollute the
environment,
and
with
the
stable
crystalline
bromoethylsulfonium salt14 as reaction substrate, which is easily
prepared on a large scale. This cyclopropanation reaction is a
more convenient and efficient process and has good yields for
preparing spirocyclopropyl oxindoles.
Scheme 1. Bioactive oxindoles and spirocyclopropyl oxindoles
Furthermore, the Carrera’s group has developed a new
methodology for the synthesis of spiro[pyrrolidin-3,3’-oxindoles]
8
with aldimines via catalytic [3+2] ring-expansion reaction.4b,
2. Results/Discussion
The group of Jian Zhou has found that the [3+2] annulation
reaction of spirocyclopropyl oxindole to provide spiro[furan-
3,3’-indolin]-2-one.9 As above, the potential of spirocyclopropyl
oxindoles in the related reactions would be fully significant.
Although different cyclopropanation strategies of oxindole10
could be provided in the reported literatures, the development of
a moderate and convenient method for the direct conversion of
unprotected oxindole into the corresponding spirocyclopropyl
oxindoles remains to be a significant challenge in organic
chemistry. The most notable methods for the preparation of
spirocyclopropyl oxindoles directly from indoles are as follows:
1) cyclopropanation of unprotected indoles with 1,2-
dibromoethane under strongly alkaline conditions, then
deprotection of N-substituted spirocyclopropyl oxindoles with
We began our experiment by examining the reaction of
oxindole (8a) and bromoethylsulfonium salt (9) under organic
base DBU in DMF solvent. We were pleased to find that the
reaction was carried out for stirring 6 h at room temperature
under air, the desired product, spiro[cyclopropane-1,3'-indoline]-
2'-one (10a), was acquired in 57% yield (Table 1, entry 1). The
structure of 10a was confirmed with 1H and 13C NMR
spectroscopic analysis, while molecular weight of compound 10a
was deduced via HR-ESI-MS. In addition, by-product, 1'-(2-
bromoethyl) spiro[cyclopropane-1,3'-indolune]-2'-one (11) was
obtained in 35% yield, the structure of which was verified by 1H
and 13C NMR spectroscopic analysis and molecular weight of
which was determined via HR-ESI-MS.

3
ring provided the corresponding compound 10v in slightly
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lower yield. In addition, halogen-substituted oxindoles generally
exhibited high reaction activities for over 70% yields.
Scheme 3. Cyclopropanation of unprotected oxindole (8a).
Inspired by this result, we first started to optimize the reaction
conditions by screening a series of solvents and bases, containing
THF, DCM, triethylamine (Et3N) and sodium hydride (NaH)
(Table 1, entries 2-5). We found that the best results, providing
compound 10a in 75% yield was obtained under organic base
Et3N in DMF solvent (Table 1, entry 3), meanwhile, compound
11 was obtained in 23% yield. In addition, we could separate
compound 11 in 28%, 26% and 22% yield under inorganic base
NaH in DMF solvent, organic base Et3N in DCM solvent and
organic base Et3N in THF solvent. In order to improve yield of
compound 10a, the reaction condition was further optimized by
adjusting the amount of the Et3N and bromoethylsulfonium salt,
for example, 2.0 equivalents bromoethylsulfonium salt produced
10a in 77% yield (Table 1, entries 6-9), but there was no
significant difference. Based on the above results, it was found
that 1.5 equivalents bromoethylsulfonium under 3.0 equivalents
Et3N in DMF solvent was the most suitable reaction condition.
Table 1. Optimization of the reaction conditions with 8aa
Table 2. reactions for the synthesis of spirocyclopropyl
oxindoles 10a
b
entry
substrate
equiv.
1.5
1.5
1.5
1.5
1.5
1.2
2.0
1.5
1.5
base
DBU
NaH
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Equiv.
3.0
solvent
DMF
DMF
DMF
DCM
THF
yield (% )
1
2
3
4
5
6
7
8
9
9
9
9
9
9
9
9
9
9
57
41
75
36
65
72
77
43
68
3.0
3.0
3.0
3.0
3.0
DMF
DMF
DMF
DMF
3.0
1.5
6.0
a Reaction conditions: 8a (0.2 mmol), with indicated amount of base and
additive, 2 mL solvent, at room temperature, under air, stirring for 6 h.
b Isolated yields are shown.
Under the optimized reaction conditions, we went on to
explore the scope of the reaction in terms of unprotected indole
substrates. As shown in Table 2, the protocol with a variety of
unprotected indoles 8 gave the corresponding spirocyclopropyl
oxindoles in good yields. Electron-donating as well as electron-
withdrawing groups on aromatic rings were tolerated, for
example, the yield of desired product 10e and 10r was good in
77% and 75% yield respectively. The substitution position of the
oxindoles was examined and had minimal influence on the
reaction yields either, oxindoles possessing various substitutions
underwent cyclopropanation in high yields. Both pyridine 10k
and 10l were acquired in 58% and 52% yield. 3H-Benzofuran-2-
one 8m was also efficiently transformed towards compound 10m
in 70% yield. A boronic ester group on C-6 position of oxindole
a
All the reactions were carried out using 8 (0.2 mmol), 9 (1.5 equiv., 0.3
mmol) and Et3N (3.0 equiv., 0.6 mmol) for stirring 6 h in 2 ml of DMF at
room temperature.

4
Tetrahedron
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We found that reaction system had a common side reaction
at 100 °C under argon for 6 h. The solution was allowed to cool
on the nitrogen of oxindole which provided over-alkylation by-
product, which was 1'-(2-bromoethyl) spiro[cyclopropane-1,3'-
indolune]-2'-one (11) in 35%, 23%, 28%, 26% and 22% yield.
Meanwhile, the N-vinyl by-product as previous reported in the
literature10h was not isolated from reaction solution. Hence, a
possible mechanism for cyclopropanation reaction, which was
different from mechanism as previous literature reports,12b, 15 was
postulated in Scheme 4. Firstly, enolate I is generated from
substrate oxindole 8a in organic base Et3N. Then, enolate I
attacks compound 9 to form intermediate II, which transform
enolate III in organic base Et3N. Finally, an intramolecular
nucleophilic substitution of enolate III provides the
spirocyclopropyl oxindole 10a.
to RT and diethyl ether (20 mL) was added to precipitate the
product 9 which was isolated by filtration as a white to grey
powder (3.22 g, 45%) after washing with Et2O and used in the
next step without further purification.19 m.p. 85-87 °C
(precipitated from toluene/Et2O) [lit.15b 86.5-88 °C (precipitated
from Et2O/CH2Cl2)]; Rf (MeOH-CH2Cl2, 1:9) 0.53. 1H NMR
(300 MHz, CDCl3): δ 8.06-8.12 (m, 4H), 7.71-7.77 (m, 6H), 4.92
(t, J = 5.9 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H); 13C NMR (75 MHz,
CDCl3): δ 135.3, 131.9, 131.1, 122.9, 48.2, 23.8. HRMS (ESI-
+
TOF) calcd for C15H14BrF3O3S2 [M-CF3O3S] : 292.9994; found:
293.0007.
4.3. General Procedure for cyclopropanation of compound 10
To a 25 mL round bottomed flask was added different
substituted oxindoles
8
(0.2 mmol, 1.0 equiv.) and
bromoethylsulfonium salt 9 (132.99 mg, 0.3 mmol, 1.5 equiv.),
DMF (2 mL). The mixture was stirred at room temperature for 5
min and Et3N (61.88 mg, 0.6 mmol, 3.0 equiv.) was added into
reaction system. The mixture was stirred for 6 hours at room
temperature until the reaction completed, quenched with
saturated ammonium chloride solution (5 mL), and was extracted
with EtOAc (3 x 30 mL). The combined organic layer washed
with H2O (2 x 10 mL), dried with anhydrous sodium sulfate.
After concentration, product was purified using column
chromatography on silica gel with suitable eluent.
4.3.1. spiro[cyclopropane-1,3'-indoline] -2'-one
Scheme 4. Proposed mechanism for cyclopropanation synthesis of oxindoles
(10a)
3. Conclusion
Colorless crystalline (24 mg, 75% yield). mp 177-180 °C.
Analytical data for 10a was consistent with that previously
reported.10h 1H NMR (300 MHz, CDCl3): δ 8.94 (s, 1H), 7.16-
7.26 (m, 1H), 6.97-7.00 (m, 2H), 6.84 (d, J = 7.4 Hz, 1H), 1.75-
1.79 (m, 2H), 1.52-1.56 (m, 2H); 13C NMR (75 MHz, CDCl3): δ
179.8, 140.8, 131.3, 126.8, 122.0, 118.6, 109.9, 27.6, 19.5.
HRMS (ESI-TOF) calcd for C10H10NO [M+H] +: 160.0757;
found: 160.0757.
In conclusion, we have developed a more convenient and
efficient method for the synthesis of spirocyclopropyl oxindoles
from N-unsubstituted oxindoles using bromoethylsulfonium salt,
which is easily commercially available and is stable for a long
time, under mild condition. A wide range of functional groups on
aromatic rings are well tolerated, and the spirocyclopropyl
oxindoles are synthetized in moderate yields. We believe that this
synthetic protocol will be adopted to construct spirooxindoles via
ring-expansion reaction with aldimines.
4.3.2. 5'-fluorospiro[cyclopropane-1,3'-indoline] -
2'-one (10b)
Colorless crystalline (28 mg, 78% yield). mp 215-218 °C.
Analytical data for 10b was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 10.54 (s, 1H),
6.92-6.99 (m, 2H), 6.84-6.87 (m, 1H), 1.59 (m, 2H), 1.49 (m,
2H); 13C NMR (75 MHz, DMSO-d6): δ 178.1, 156.9-160.0 (d, JC-
F = 233.9 Hz), 138.3, 133.4-133.5 (d, JC-F = 9.3 Hz), 112.9-133.3
(d, JC-F = 23.3 Hz), 110.2-110.3 (d, JC-F = 8.3 Hz), 107.6-108.0
(d, JC-F = 25.3 Hz), 28.1, 19.2. HRMS (ESI-TOF) calcd for
C10H9NFO [M+H] +: 178.0663; found: 178.0663.
4. Experimental Section
4.1. General
All reagents and solvents were of commercial quality and
were used without further purification unless otherwise stated.
Purification was carried out according to standard laboratory
methods.16 Reactions were carried out using conventional
glassware under air atmosphere at room temperature. All
reactions were monitored by TLC analysis with silica gel-coated
plates with fluorescent indicator UV254. 1H and 13C NMR
spectra were obtained on either a Bruker AV 300 at 300 MHz
and 75 MHz, respectively. 1H and 13C NMR spectra were
obtained on either a Bruker AV 300 at 300 MHz and 75 MHz,
respectively. Chemical shifts are reported in ppm and coupling
constants are reported in Hz with TMS at 0.0 ppm (1H and 13C) or
CDCl3 referenced at 7.26 (1H) and 77.0 ppm (13C) and DMSO-d6
referenced at 2.50 (1H) and 39.5 (13C). Mass spectra were
measured with an Agilent Q-TOF 6520 mass spectrometer using
ESI ionization.
4.3.3. 5'-chlorospiro[cyclopropane-1,3'-indoline] -
2'-one (10c)
1
Pale yellow solid (31 mg, 78% yield). mp 212-215 °C. H
NMR (300 MHz, DMSO-d6): δ 10.67 (s, 1H), 7.19 (d, J = 8.0 Hz,
1H), 7.10 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 1.63 (m, 2H), 1.48
(m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 177.9, 141.0, 133.7,
126.7, 125.8, 120.1, 110.9, 27.7, 19.3. HRMS (ESI-TOF) calcd
for C10H9NClO [M+H] +: 194.0367; found: 194.0371.
4.3.4. 5'-bromospiro[cyclopropane-1,3'-indoline] -
2'-one (10d)
Colorless crystalline (35 mg, 72% yield). mp 207-209 °C. 1H
NMR (300 MHz, DMSO-d6): δ 10.67 (s, 1H), 7.32 (d, J = 8.2 Hz,
1H), 7.21 (s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 1.64 (m, 2H), 1.48
(m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 177.3, 140.9, 133.6,
129.1, 122.3, 113.0, 111.0, 27.1, 18.8. HRMS (ESI-TOF) calcd
for C10H9NBrO [M+H] +: 237.9862; found: 237.9859.
4.2. Preparation of bromoethylsulfonium salt (9)17
A solution of 2-bromoethyl trifluoromethanesulfonate15,
(4.12 g, 16.0 mmol) in anhydrous toluene (12 mL) was treated
with phenyl sulfide (3.66 g, 19.2 mmol) at room temperature
under argon with stirring. The reaction mixture was then heated
18

5
4.3.5. 5'-nitrospiro[cyclopropane-1,3'-indoline] -2'-
NMR (75 MHz, DMSO-d6): δ 178.1, 139.6, 133.4, 127.0,
ACCEPTED MANUSCRIPT
one (10e)
White solid (32 mg, 77% yield). mp 241-244 °C. Analytical
data for 10e was consistent with that previously reported.10h 1
122.9, 118.3, 114.1, 28.2, 19.5. HRMS (ESI-TOF) calcd for
C10H9NClO [M+H] +: 194.0367; found: 194.0380.
H
4.3.12. 4'-chlorospiro[cyclopropane-1,3'-indoline] -
NMR (300 MHz, DMSO-d6): δ 11.28 (s, 1H), 8.17 (d, J = 4.9 Hz,
1H), 7.99 (s, 1H), 7.12 (d, J = 7.1 Hz, 1H), 1.86 (m, 2H), 1.61
(m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 178.5, 148.5, 142.4,
132.6, 124.4, 115.8, 109.6, 27.8, 20.0. HRMS (ESI-TOF) calcd
for C10H9N2O3 [M+H] +: 205.0608; found: 205.0744.
2'-one (10l)
1
Pale yellow solid (31 mg, 78% yield). mp 203-205 °C. H
NMR (300 MHz, DMSO-d6): δ 10.82 (s, 1H), 7.15-7.20 (m, 1H),
6.89-6.94 (m, 2H), 2.05-2.08 (m, 2H), 1.37-1.41 (m, 2H); 13C
NMR (75 MHz, DMSO-d6): δ 177.2, 144.3, 128.7, 126.6, 126.1,
122.3, 109.1, 28.2, 15.2. HRMS (ESI-TOF) calcd for C10H9NClO
[M+H] +: 194.0367; found: 194.0362.
4.3.6. 5'-methylspiro[cyclopropane-1,3'-indoline] -
2'-one (10f)
Pale yellow crystalline (26 mg, 73% yield). mp 195-198 °C.
1H NMR (300 MHz, DMSO-d6): δ 10.43 (s, 1H), 6.96 (dd, J =
0.9, 7.8 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.77 (br s, 1H), 2.23
(s, 3H), 1.50 (m, 2H), 1.44 (m, 2H); 13C NMR (75 MHz, DMSO-
d6): δ 178.4, 139.9, 131.6, 130.5, 127.4, 120.4, 109.6, 27.5, 21.4,
18.8. HRMS (ESI-TOF) calcd for C11H12NO [M+H] +: 174.0913;
found: 174.0912.
4.3.13. 4'-fluorospiro[cyclopropane-1,3'-indoline] -
2'-one (10m)
Colorless crystalline (27 mg, 74% yield). mp 168-170 °C.
Analytical data for 10m was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 10.78 (s, 1H),
7.18 (td, J = 8.1, 5.8 Hz, 1H), 6.75 (dd, J = 16.7, 8.2 Hz, 2H),
1.76 (td, J = 7.6, 3.8 Hz, 2H), 1.45 (td, J = 7.6, 3.8 Hz, 2H); 13C
NMR (75 MHz, DMSO-d6): δ 177.5, 158.6, 144.5-144.6 (d, JC-F
4.3.7. 5'-methoxyspiro[cyclopropane-1,3'-indoline] -
2'-one (10g)
= 9.3 Hz), 128.7-128.8 (d, JC-F = 8.3 Hz), 116.1-116.4 (d, JC-F
=
Colorless crystalline (29 mg, 75% yield). mp 158-160 °C. 1H
NMR (300 MHz, DMSO-d6): δ 10.33 (s, 1H), 6.80 (d, J = 8.4 Hz,
1H), 6.68-6.75 (m, 1H), 6.64 (d, J = 2.2 Hz, 1H), 3.69 (s, 3H),
1.51-1.55 (m, 2H), 1.41-1.49 (m, 2H); 13C NMR (75 MHz,
DMSO-d6): δ 178.3, 155.3, 135.6, 132.9, 112.0, 110.1, 106.9,
56.0, 28.0, 18.9. HRMS (ESI-TOF) calcd for C11H12NO2 [M+H]
+: 190.0863; found: 190.0864.
17.9 Hz), 108.6-108.8 (d, JC-F = 19.7 Hz), 106.7, 26.4, 16.5.
HRMS (ESI-TOF) calcd for C10H9NFO [M+H] +: 178.0663;
found: 178.0662.
4.3.14. 4'-bromospiro[cyclopropane-1,3'-indoline] -
2'-one (10n)
White solid (38 mg, 79% yield). mp 195-198 °C. Analytical
data for 10n was consistent with that previously reported.10h 1
H
4.3.8. 6'-fluorospiro[cyclopropane-1,3'-indoline] -
2'-one (10h)
NMR (300 MHz, DMSO-d6): δ 10.85 (s, 1H), 7.14-7.17 (m, 2H),
6.98-7.00 (m, 1H), 2.17 (m, 2H), 1.40 (m, 2H); 13C NMR (75
MHz, DMSO-d6): δ 177.2, 144.6, 129.0, 127.4, 125.5, 114.8,
109.5, 28.9, 15.0. HRMS (ESI-TOF) calcd for C10H9NBrO
[M+H] +: 237.9862; found: 237.9863.
Pale yellow solid (23 mg, 63% yield). mp 173-175 °C.
Analytical data for 10h was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 10.67 (s, 1H),
6.95-6.97 (m, 1H), 6.70-6.73 (m, 1H), 1.54 (m, 2H), 1.45 (m,
2H); 13C NMR (75 MHz, DMSO-d6): δ 178.6, 160.3-163.5 (d, JC-
F = 238.1 Hz), 143.3-143.5 (d, JC-F = 12.2 Hz), 127.0-127.1 (d, JC-
4.3.15. 4'-methylspiro[cyclopropane-1,3'-indoline] -
2'-one (10o)
Colorless crystalline (25 mg, 72% yield). mp 170-172 °C. 1H
NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 7.03 (t, J = 7.7 Hz,
1H), 6.68-6.76 (m, 2H), 2.12 (s, 3H), 1.93 (m, 2H), 1.29 (m, 2H);
13C NMR (75 MHz, DMSO-d6): δ 178.1, 142.5, 132.0, 126.9,
126.8, 124.0, 107.8, 28.1, 16.8, 14.7. HRMS (ESI-TOF) calcd for
C11H12NO [M+H] +: 174.0913; found: 174.0911.
F = 2.3 Hz), 120.7-120.8 (d, JC-F = 9.6 Hz), 107.4-107.7 (d, JC-F
=
22.3 Hz), 97.8-98.2 (d, JC-F = 27.0 Hz), 27.1, 18.7. HRMS (ESI-
TOF) calcd for C10H9NFO [M+H] +: 178.0663; found: 178.0659.
4.3.9. 6'-chlorospiro[cyclopropane-1,3'-indoline] -
2'-one (10i)
Colorless crystalline (27 mg, 71% yield). mp 225-228 °C.
Analytical data for 10i was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 10.73 (s, 1H), 7.02
(br s, 2H), 6.95 (br s, 1H), 1.62 (m, 2H), 1.53 (m, 2H); 13C NMR
(75 MHz, DMSO-d6): δ 178.1, 143.5, 131.2, 130.3, 121.2, 121.1,
109.8, 27.3, 19.1. HRMS (ESI-TOF) calcd for C10H9NClO
[M+H] +: 194.0367; found: 194.0363.
4.3.16. 5',6'-dichlorospiro[cyclopropane-1,3'-
indoline] -2'-one (10p)
Colorless crystalline (38 mg, 82% yield). mp 245-247 °C.
Analytical data for 10p was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 10.78 (s, 1H),
7.31 (s, 1H), 7.06 (s, 1H), 1.66-1.70 (m, 2H), 1.49-1.53 (m, 2H);
13C NMR (75 MHz, DMSO-d6): δ 177.8, 142.2, 132.6, 129.0,
123.6, 121.9, 111.2, 27.6, 19.6. HRMS (ESI-TOF) calcd for
C10H8Cl2NO [M+H] +: 227.9977; found: 227.9975.
4.3.10. 6'-bromospiro[cyclopropane-1,3'-indoline] -
2'-one (10j)
White solid (35 mg, 72% yield). mp 243-246 °C. Analytical
data for 10j was consistent with that previously reported.10h 1H
NMR (300 MHz, DMSO-d6): δ 10.68 (s, 1H), 7.12 (d, J = 7.6 Hz,
1H), 7.04 (s, 1H), 6.94 (d, J = 5.8 Hz, 1H), 1.58 (m, 2H), 1.49
(m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 178.0, 143.8, 130.8,
124.0, 121.5, 119.3, 112.5, 27.1, 18.8. HRMS (ESI-TOF) calcd
for C10H9NBrO [M+H] +: 237.9862; found: 237.9860.
4.3.17. 5',6'-difluorospiro[cyclopropane-1,3'-
indoline] -2'-one (10q)
Colorless crystalline (31 mg, 80% yield). mp 248-250 °C.
Analytical data for 10q was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 1H),
7.21 (dd, JH-F = 8.1, 10.2 Hz, 1H), 6.94 (dd, JH-F = 6.8, 10.6 Hz,
1H), 1.63-1.65 (m, 2H), 1.51-1.53 (m, 2H); 13C NMR (75 MHz,
DMSO-d6): δ 178.3, 150.4-150.6 (d, JC-F = 14.0 Hz), 147.2-147.4
(d, JC-F = 13.9 Hz), 138.3-138.4 (d, JC-F = 10.2 Hz), 127.5-127.6
(d, JC-F = 7.5 Hz), 109.5-109.8 (d, JC-F = 20.6 Hz), 99.4-99.7 (d,
JC-F = 22.5 Hz), 27.6, 19.2. HRMS (ESI-TOF) calcd for
C10H8F2NO [M+H] +: 196.0568; found: 196.0565.
4.3.11. 7'-chlorospiro[cyclopropane-1,3'-indoline] -
2'-one (10k)
Pale yellow crystalline (26 mg, 67% yield). mp 163-165 °C.
Analytical data for 10k was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 11.03 (s, 1H),
7.25 (m, 2H), 6.99-7.00 (m, 2H), 1.66 (m, 2H), 1.58 (m, 2H); 13
C

6
Tetrahedron
ACCEPTED MANUSCRIPT
4.3.18. spiro[1H-pyrrolo[2,3-b]pyridine-3,1'-
Appendix A. Supplementary data
cyclopropane] -2-one (10r)
Supplementary data related to this article can be found at DOI:
Pale Yellow crystalline. (19 mg, 58% yield). mp 170-173 °C.
Analytical data for 10r was consistent with that previously
reported.10h 1H NMR (300 MHz, DMSO-d6): δ 11.14 (s, 1H),
8.04 (br s, 1H), 7.33-7.36 (m, 1H), 6.92 (br s, 1H), 1.63 (m, 2H),
1.52 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 177.9, 156.8,
145.7, 127.2, 125.7, 117.6, 27.0, 18.7. HRMS (ESI-TOF) calcd
for C9H9N2O [M+H] +: 161.0709; found: 161.0708.
References
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2.
3.
4.3.19. 5-bromospiro[1H-pyrrolo[2,3-b]pyridine-
3,1'-cyclopropane] -2-one (10s)
Red crystalline. (25 mg, 52% yield). mp 238-240 °C. 1H NMR
(300 MHz, DMSO-d6): δ 11.35 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H),
7.66 (d, J = 1.9 Hz, 1H), 1.73-1.76 (m, 2H), 1.55-1.57 (m, 2H);
13C NMR (75 MHz, DMSO-d6): δ 177.6, 155.8, 145.9, 130.1,
128.3, 112.6, 27.3, 19.4. HRMS (ESI-TOF) calcd for C9H8BrN2O
[M+H] +: 238.9815; found: 238.9814.
4.
4.3.20. Spiro[benzofuran-3,1'-cyclopropan]-2-one
(10t)
5.
6.
Yellow crystalline (23 mg, 70% yield). mp 83-85 °C.
Analytical data for 10t was consistent with that previously
reported20. 1H NMR (300 MHz, DMSO-d6): δ 11.35 (s, 1H), 8.15
(d, J = 2.2 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 1.73-1.76 (m, 2H),
1.55-1.57 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 177.9,
153.6, 129.2, 127.8, 124.2, 119.1, 110.8, 25.1, 21.2. HRMS (ESI-
TOF) calcd for C10H9lO2 [M+H] +: 161.0597; found: 161.0597.
7.
4.3.21. Methyl 2'-oxospiro[cyclopropane-1,3'-
indoline] -6'-carboxylate (10u)
1
Colorless crystalline (36 mg, 81% yield). mp 226-230 °C. H
NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 7.57 (dd, J = 1.5,
7.8 Hz, 1H), 7.43 (d, J = 1.1 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H),
3.84 (s, 3H), 1.66-1.68 (m, 2H), 1.55-1.58 (m, 2H); 13C NMR (75
MHz, DMSO-d6): δ 177.9, 166.7, 142.5, 137.3, 128.4, 123.1,
119.7,109.6, 52.6, 27.9, 19.8. HRMS (ESI-TOF) calcd for
C12H12NO3 [M+H] +: 218.0812; found: 218.0811.
8.
4.3.22. 6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)spiro[cyclopropane-1,3'-indoline] -6'-
carboxylate (10v)
9.
10.
1
Colorless crystalline (29 mg, 49% yield). mp 252-254 °C. H
NMR (300 MHz, DMSO-d6): δ 10.59 (s, 1H), 7.26 (d, J = 7.4 Hz,
1H), 7.17 (s, 1H), 6.97 (d, J = 7.4 Hz, 1H), 1.57-1.60 (m, 2H),
1.48-1.52 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 178.0,
141.9, 135.2, 128.1, 119.2, 114.8, 84.0, 27.8, 25.1, 19.2. HRMS
(ESI-TOF) calcd for C16H21BNO3 [M+H] +: 286.1612; found:
286.1617.
4.3.23. 1'-(2-bromoethyl) spiro[cyclopropane-1,3'-
indolin] -2'-one (11)
1
Yellow oil. (19 mg, 35% yield). H NMR (300 MHz, CDCl3):
δ 7.26-7.31 (m, 1H), 7.00-7.09 (m, 2H), 6.97 (d, J = 7.3 Hz, 1H),
4.21 (t, J = 7.2 Hz, 2H), 3.61 (t, J = 7.2 Hz, 2H), 1.78-1.81 (m,
2H), 1.56-1.57 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 177.0,
142.2, 130.7, 126.8, 122.3, 118.6, 108.2, 42.1, 27.6, 27.0, 18.7.
HRMS (ESI-TOF) calcd for C12H13BrNO [M+H] +: 266.0175;
found: 266.0181.
11.
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Acknowledgements
This research work was financially supported by National
Natural Science Foundation of China (No. 81502950, 81703382),
and the Priority Academic Program Decelopment of Jiangsu
Higher Education Instiutions.
13.
14.
15.
P. Jia, Q. Zhang, H. Jin, Y. Huang, Org. Lett. 2017, 19, 412-415.
This salt is now commercially available from Aldrich.
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